Each cell in our body is constantly exposed to a myriad of endogenous and exogenous factors that result in the accumulation of thousands of diverse DNA lesions per day. DNA damage is a causative factor in aging and carcinogenesis and plays a critical role in many disorders such as neurodegenerative and cardiovascular disease. Inter-individual variation in sensitivity to DNA damage is significant, with profound ramifications for cancer incidence and treatment, ageing, and public health in general. The damage response (DDR) is the concerted cellular program that mitigates the effects of DNA damage by integrating many damage detection, signaling and cell cycle checkpoint proteins with various DNA repair mechanisms. The majority of the signaling between DDR components is mediated at the post-translational level through phosphorylation. Currently, we have identified very few of the genetic variants driving differential sensitivity to DNA damage and know very little about their DDR context specific mechanisms. Addressing these questions will have direct and immediate application within a personalized medicine framework. The proposed research will identify regions of the genome that correlate with inter-individual variation in response to DNA damage at the post-translational penetrance level. Cells derived from fully sequenced individuals will be subject to quantitative phosphoproteomic analysis before and after DNA damage. Using a quantitative trail locus (QTL) mapping approach, genetic variants associated with differential phosphopeptide levels and sensitivity to DNA damage will be identified. Using the DDR as a guide, a limited subset of QTLs will be characterized to identify their mode of action.